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PPARγ: a circadian transcription factor in adipogenesis and osteogenesis

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ agonists, the thiazolidinediones, have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose levels. However, the use of thiazolidinediones has been associated with bone loss and fractures. Thiazolidinedione-induced alterations in the bone marrow milieu—that is, increased bone marrow adiposity with suppression of osteogenesis—could partially explain the pathogenesis of drug-induced bone loss. Furthermore, several lines of evidence place PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One gene with circadian regulation in peripheral tissues, nocturnin, has been shown to enhance PPARγ activity. Importantly, mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.

Key Points

  • Activation of PPARγ is a therapeutic target in type 2 diabetes mellitus

  • Activation of PPARγ is a risk factor for osteoporosis

  • PPARγ is a key factor in the determination of mesenchymal stem cell fate

  • A role for bone marrow adipocytes in skeletal metabolism is emerging

  • PPARγ provides a link between the circadian clock system and metabolic output

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Figure 1: Schematic model of the role of PPARγ in bone marrow.
Figure 2: Nocturnin regulates PPARγ's circadian profile and activity.

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Acknowledgements

C. J. Rosen is supported by NIH grants R24DK084970 and AR45433.

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M. Kawai and C. J. Rosen contributed equally to researching the data for the article, discussions of the content, writing of the article and reviewing and/or editing of the manuscript before submission.

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Correspondence to Clifford J. Rosen.

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Kawai, M., Rosen, C. PPARγ: a circadian transcription factor in adipogenesis and osteogenesis. Nat Rev Endocrinol 6, 629–636 (2010). https://doi.org/10.1038/nrendo.2010.155

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